T2-Pseudonormalization and Microstructural Characterization in Advanced Stages of Late-infantile Metachromatic Leukodystrophy

Pascal Martin, Gisela E. Hagberg, Thomas Schultz, Klaus Harzer, Uwe Klose, Benjamin Bender, Thomas Nägele, Klaus Scheffler, Ingeborg Krägeloh-Mann, and Samuel Gröschel
In: Clinical Neuroradiology (Nov. 2020)
 

Abstract

Purpose: T2-weighted signal hyperintensities in white matter (WM) are a diagnostic finding in brain magnetic resonance imaging (MRI) of patients with metachromatic leukodystrophy (MLD). In our systematic investigation of the evolution of T2-hyperintensities in patients with the late-infantile form, we describe and characterize T2-pseudonormalization in the advanced stage of the natural disease course.

Methods: The volume of T2-hyperintensities was quantified in 34 MRIs of 27 children with late-infantile MLD (median age 2.25 years, range 0.5–5.2 years). In three children with the most advanced clinical course (age >4 years) and for whom the T2-pseudonormalization was the most pronounced, WM microstructure was investigated using a multimodal MRI protocol, including diffusion-weighted imaging, MR spectroscopy (MRS), myelin water fraction (MWF), magnetization transfer ratio (MTR), T1-mapping and quantitative susceptibility mapping.

Results: T2-hyperintensities in cerebral WM returned to normal in large areas of 3 patients in the advanced disease stage. Multimodal assessment of WM microstructure in areas with T2-pseudonormalization revealed highly decreased values for NAA, neurite density, isotropic water, mean and radial kurtosis, MWF and MTR, as well as increased radial diffusivity.

Conclusion: In late-infantile MLD patients, we found T2-pseudonormalization in WM tissue with highly abnormal microstructure characterizing the most advanced disease stage. Pathological hallmarks might be a loss of myelin, but also neuronal loss as well as increased tissue density due to gliosis and accumulated storage material. These results suggest that a multimodal MRI protocol using more specific microstructural parameters than T2-weighted sequences should be used when evaluating the effect of treatment trials in MLD.

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Bibtex

@ARTICLE{Martin:CN2020,
    author = {Martin, Pascal and Hagberg, Gisela E. and Schultz, Thomas and Harzer, Klaus and Klose, Uwe and
              Bender, Benjamin and N{\"a}gele, Thomas and Scheffler, Klaus and Kr{\"a}geloh-Mann, Ingeborg and
              Gr{\"o}schel, Samuel},
     title = {T2-Pseudonormalization and Microstructural Characterization in Advanced Stages of Late-infantile
              Metachromatic Leukodystrophy},
   journal = {Clinical Neuroradiology},
      year = {2020},
     month = nov,
  abstract = {Purpose: T2-weighted signal hyperintensities in white matter (WM) are a diagnostic finding in brain
              magnetic resonance imaging (MRI) of patients with metachromatic leukodystrophy (MLD). In our
              systematic investigation of the evolution of T2-hyperintensities in patients with the late-infantile
              form, we describe and characterize T2-pseudonormalization in the advanced stage of the natural
              disease course.
              
              Methods: The volume of T2-hyperintensities was quantified in 34 MRIs of 27 children with
              late-infantile MLD (median age 2.25 years, range 0.5–5.2 years). In three children with the most
              advanced clinical course (age >4 years) and for whom the T2-pseudonormalization was the most
              pronounced, WM microstructure was investigated using a multimodal MRI protocol, including
              diffusion-weighted imaging, MR spectroscopy (MRS), myelin water fraction (MWF), magnetization
              transfer ratio (MTR), T1-mapping and quantitative susceptibility mapping.
              
              Results: T2-hyperintensities in cerebral WM returned to normal in large areas of 3 patients in the
              advanced disease stage. Multimodal assessment of WM microstructure in areas with
              T2-pseudonormalization revealed highly decreased values for NAA, neurite density, isotropic water,
              mean and radial kurtosis, MWF and MTR, as well as increased radial diffusivity.
              
              Conclusion: In late-infantile MLD patients, we found T2-pseudonormalization in WM tissue with highly
              abnormal microstructure characterizing the most advanced disease stage. Pathological hallmarks might
              be a loss of myelin, but also neuronal loss as well as increased tissue density due to gliosis and
              accumulated storage material. These results suggest that a multimodal MRI protocol using more
              specific microstructural parameters than T2-weighted sequences should be used when evaluating the
              effect of treatment trials in MLD.}
}